US4438135A - 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes - Google Patents

1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes Download PDF

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Publication number
US4438135A
US4438135A US06/456,199 US45619983A US4438135A US 4438135 A US4438135 A US 4438135A US 45619983 A US45619983 A US 45619983A US 4438135 A US4438135 A US 4438135A
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United States
Prior art keywords
compound
bis
phenyl
thioureido
anthelmintic
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Expired - Fee Related
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US06/456,199
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English (en)
Inventor
Alfred W. Chow
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Assigned to SMITHKLINE BECKMAN CORPORATION, A CORP OF PA. reassignment SMITHKLINE BECKMAN CORPORATION, A CORP OF PA. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: CHOW, ALFRED W.
Priority to US06/456,199 priority Critical patent/US4438135A/en
Priority to CA000443171A priority patent/CA1205481A/en
Priority to ZA847A priority patent/ZA847B/xx
Priority to GR73421A priority patent/GR81705B/el
Priority to ES528675A priority patent/ES8507482A1/es
Priority to AU23060/84A priority patent/AU567532B2/en
Priority to EP84300077A priority patent/EP0113697B1/en
Priority to DE8484300077T priority patent/DE3460012D1/de
Priority to JP59000507A priority patent/JPS59130860A/ja
Priority to AT84300077T priority patent/ATE16797T1/de
Priority to IE11/84A priority patent/IE56516B1/xx
Priority to PT77929A priority patent/PT77929B/pt
Priority to DK5984A priority patent/DK5984A/da
Publication of US4438135A publication Critical patent/US4438135A/en
Application granted granted Critical
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
    • C07C335/28—Y being a hetero atom, e.g. thiobiuret
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • This invention relates to 1,1-diphenylethylene anthelmintic compounds whose structures are distinguished by having one of the phenyl rings substituted by two adjacent lower alkoxycarbonylthioureido groups.
  • the compounds have anthelmintic activity against nematodes, cestodes and flukes.
  • a series of 5-acyl benzimidazoles which have a carbamyl substituent at the 2-position are described as anthelmintic agents, U.S. Pat. No. 3,657,267.
  • the marketed species of this group is mebendazole which is methyl (5-benzoyl-1H-benzimidazol-2-yl)carbamate.
  • German patent application DT 2303048 discloses certain anthelmintic benzophenone structures which have a bis acylamino substitution pattern.
  • U.S. Pat. Nos. 3,961,063 and 4,002,761 describe anthelmintic compounds whose structures have a pyridine ring substituted by both a benzophenone, among others, and two bisacylamino groups. None of this art suggests the preparation of the 1,1-diphenylethylene compounds of this invention.
  • This invention relates to 1-(3,4-bis-(3-lower alkoxycarbonyl)-2-thioureido)phenyl)-1-phenylethylenes which have anthelmintic activity. These compounds have a low chemical cost which is advantageous in this field.
  • R is hydrogen, halo such as fluoro, chloro or bromo, C 1-4 -alkoxy, C 1-4 -alkyl or C 1-4 -alkylthio, and
  • Alk is, each, a branched or straight lower alkyl of 1-6 carbons.
  • the compounds of this invention are prepared by reacting a 1-(3,4-diaminophenyl)-1-phenylethylene with at least two molar equivalents of an alkoxycarbonylisothiocyanate, prepared from an alkali metal thiocyanate and a lower alkyl chloroformate, in an inert organic solvent, such as acetone, at a temperature of the range from room to reflux temperature until the reaction is complete.
  • an inert organic solvent such as acetone
  • the 1,1-diphenylethylene compounds of this invention were evaluated using the method of testing described by V. J. Theodorides, "Anthelmintics: From Laboratory Animals to the Target Species," Chapter 5, Chemotherapy of Infectious Diseases, H. H. Gadebusch, Ed, C.R.C. Press, 1976.
  • the 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2-thioureido)phenyl)-1-phenylethylenes of formula I have useful general anthelmintic properties, that is, a broad spectrum of activity against parasites of warm-blooded animals.
  • these compounds have high activity against various helmintic infections of the intestinal tract of mammalian hosts, coupled with low systemic toxicity to the host.
  • Such hosts include man, horses, swine, sheep, dogs, goats, cats and cattle. The activity is observed against nematodes, cestodes and flukes.
  • the disclosed compounds are generally effective in clearing mice of worm infections for laboratory purposes, among others: Syphacia obvelata and Aspicularis tetraptera (mouse pinworm), Nematospiroides dubius (mouse hookworm), and the migratory stages of Ascaris suum.
  • Toxocara canis found in naturally infested dogs.
  • parasitic to this host are Ancylostoma canium, Trichuris vulpis (whipworm), and Physalaptera spp.
  • Compounds of Formula I are most efficacious against parasitic gastroenteritis in sheep, such as Haemonchus contortus, Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Trichuris ovis, Cooperia spp., Strongyloides papillosus, Bunostomum trigoncephalum and Oesophagostomum spp.
  • Animals of low weight are treated with unit doses ranging no higher than a few milligrams; whereas animals of high body weight, such as ruminants, require proportionately large unit doses ranging up to one or more grams daily.
  • a single oral dose selected from the range of 1-10 mg./kg. is administered daily to each animal based on the general body weight of that species.
  • an active compound of the structure of formula I is usually formulated with a non-toxic carrier therefor to give an anthelmintic composition of this invention.
  • the carrier may be an orally ingestible container for the active ingredient, for example, a pill or a gelatin capsule; or it may be a pharmaceutically acceptable diluent or excipient of the kind normally used in the production of medicaments, for example, maize, starch, terra alba, lactose, sucrose, calcium phosphate, gelatin, talcum, stearic acid, magnesium stearate, dextrin, agar, pectin or acacia.
  • liquid carriers are peanut oil, olive oil, sesame oil and water.
  • the carrier or diluent may include a time delay or continuous release matrix material such as glyceryl monostearate or glyceryl distearate, alone or admixed with a wax.
  • compositions are made up in a dosage unit form adapted for the desired mode of administration.
  • the dosage unit may take the form of a suspension, tablet, packaged powder, bolus or encapsulated powder.
  • the quantity of active ingredient in each dosage unit will be such that one or more units can be used for each therapeutic administration.
  • the compounds of formula I have general anthelmintic activity and are used for treating or preventing helmintic infections in an animal or human host. They are administered, usually orally, to the host in a nontoxic, but effective, quantity in the form of a pharmaceutical or veterinary composition as herein described.
  • the daily dose range commonly used is selected from the range of about 1 mg./kg. to about 25 mg./kg., preferably about 5 mg./kg.-15 mg./kg., depending on the infection, the species of host and regimen described. One oral dose per day is preferred.
  • the daily dose range is, therefore, often identical to the dosage unit range.
  • mg./kg. is used to indicate weight of active ingredient per each kilogram of body weight of the infected or potentially infected subject.
  • Potassium thiocyanate (10.0 g., 0.104 mole) was dissolved in acetone (250 ml.). Methyl chloroformate (10.0 g., 0.104 mole) was added and the solution was heated at reflux for 1/2 hour. After the potassium chloride had been removed by filtration, 10.5 g. (0.5 mole) of 1-(3,4-diaminophenyl)-1-phenylethylene was added. The resulting solution was stirred overnight at room temperature. Additional potassium chloride was filtered off and the filtrate concentrated to give a tan solid.
  • the calcium phosphate and the anthelmintic compound are thoroughly mixed, and the mixture reduced to a particle size finer than 60 mesh.
  • About one-half of the starch is added, as an aqueous paste, and the resulting mixture granulated.
  • the granules are passed through a 10 mesh screen and dried at 110°-130° F. for about eight hours.
  • the dried materials are then passed through a No. 16 mesh screen.
  • the guar gum and the balance of the starch are added and the mixture thoroughly blended. Finally, the remainder of the ingredients are added and the entire mass thoroughly mixed and compressed into a bolus.
  • the magnesium stearate, talcum and gum acacia are of a particle size to pass a No. 10 mesh screen.
  • This powder can be directly admixed with water in concentration on the order of 10.5 g. of powder to 5 cc. of water.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Dental Preparations (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
US06/456,199 1983-01-07 1983-01-07 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes Expired - Fee Related US4438135A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US06/456,199 US4438135A (en) 1983-01-07 1983-01-07 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes
CA000443171A CA1205481A (en) 1983-01-07 1983-12-13 1-(3,4-bis-(3-lower alkoxycarbonyl)-2-thio-ureido)- phenyl)-1-phenylethylenes
ZA847A ZA847B (en) 1983-01-07 1984-01-03 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl)-1-phenylethylenes
GR73421A GR81705B (cs) 1983-01-07 1984-01-03
ES528675A ES8507482A1 (es) 1983-01-07 1984-01-04 Metodo de preparar 1-(3,4-bis-(3-(alcoxicarbonilo inferior)-2-tioureido)-fenil)-1-feniletilenos
AU23060/84A AU567532B2 (en) 1983-01-07 1984-01-04 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2thio-ureido)- phenyl)-1-phenylethylenes
EP84300077A EP0113697B1 (en) 1983-01-07 1984-01-05 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylethylenes
DE8484300077T DE3460012D1 (de) 1983-01-07 1984-01-05 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylethylenes
JP59000507A JPS59130860A (ja) 1983-01-07 1984-01-05 フエニルエチレン化合物
AT84300077T ATE16797T1 (de) 1983-01-07 1984-01-05 1-(3,4-bis-(3-(alkoxycarbonyl)-2-thioureido)phenyl-1-phenylethylen.
IE11/84A IE56516B1 (en) 1983-01-07 1984-01-05 1-(3,4-bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl)-1-phenylethylenes
PT77929A PT77929B (en) 1983-01-07 1984-01-06 1-<<3,4-bis-<3-(lower alkoxycarbonyl)-2-thioureido>-phenyl>>-1-phenylethylenes
DK5984A DK5984A (da) 1983-01-07 1984-01-06 1-(3,4-bis-(3-(lavere alkoxycarbonyl)-2-thioureido)phenyl)-1-phenylethylener

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/456,199 US4438135A (en) 1983-01-07 1983-01-07 1-(3,4-Bis-(3-(lower alkoxycarbonyl)-2-thioureido)-phenyl-1-phenylthylenes

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US4438135A true US4438135A (en) 1984-03-20

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Country Status (13)

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US (1) US4438135A (cs)
EP (1) EP0113697B1 (cs)
JP (1) JPS59130860A (cs)
AT (1) ATE16797T1 (cs)
AU (1) AU567532B2 (cs)
CA (1) CA1205481A (cs)
DE (1) DE3460012D1 (cs)
DK (1) DK5984A (cs)
ES (1) ES8507482A1 (cs)
GR (1) GR81705B (cs)
IE (1) IE56516B1 (cs)
PT (1) PT77929B (cs)
ZA (1) ZA847B (cs)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611754A1 (en) * 1993-02-19 1994-08-24 Nippon Paper Industries Co., Ltd. Dimerized thiourea derivatives, near-infrared absorbents comprising the same, and heat wave shielding materials comprising the same

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657267A (en) 1969-06-20 1972-04-18 Janssen Pharmaceutica Nv Benzimidazole carbamates
US3856847A (en) 1968-10-28 1974-12-24 Nippon Soda Co Metal salts of bis-thioureido benzenes
US3961063A (en) 1975-04-03 1976-06-01 Smithkline Corporation 2,3-Bis-(3-acyl-2-thioureido)-pyridines
US4002761A (en) 1975-04-03 1977-01-11 Smithkline Corporation 2,3-Bis-(3-lower alkanoyl-2-thioureido)-pyridines
US4020095A (en) 1967-10-30 1977-04-26 Nippon Soda Company Limited Bis-thioureido-benzenes, preparation and uses thereof
US4029813A (en) 1967-10-30 1977-06-14 Nippon Soda Company Limited Fungicidal compositions containing bisthioureido-benzenes and methods for use thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1307250A (en) * 1970-06-16 1973-02-14 May & Baker Ltd Benzene derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4020095A (en) 1967-10-30 1977-04-26 Nippon Soda Company Limited Bis-thioureido-benzenes, preparation and uses thereof
US4029813A (en) 1967-10-30 1977-06-14 Nippon Soda Company Limited Fungicidal compositions containing bisthioureido-benzenes and methods for use thereof
US3856847A (en) 1968-10-28 1974-12-24 Nippon Soda Co Metal salts of bis-thioureido benzenes
US3657267A (en) 1969-06-20 1972-04-18 Janssen Pharmaceutica Nv Benzimidazole carbamates
US3961063A (en) 1975-04-03 1976-06-01 Smithkline Corporation 2,3-Bis-(3-acyl-2-thioureido)-pyridines
US4002761A (en) 1975-04-03 1977-01-11 Smithkline Corporation 2,3-Bis-(3-lower alkanoyl-2-thioureido)-pyridines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Derwent Abstract No. 55442V/31.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611754A1 (en) * 1993-02-19 1994-08-24 Nippon Paper Industries Co., Ltd. Dimerized thiourea derivatives, near-infrared absorbents comprising the same, and heat wave shielding materials comprising the same
US5723075A (en) * 1993-02-19 1998-03-03 Nippon Paper Industries Co., Ltd. Dimerized thiourea derivatives near-infared absorbents comprising the same, and heat wave shielding materials comprising the same

Also Published As

Publication number Publication date
ES528675A0 (es) 1985-09-01
ZA847B (en) 1984-08-29
IE840011L (en) 1984-07-07
DK5984D0 (da) 1984-01-06
IE56516B1 (en) 1991-08-28
CA1205481A (en) 1986-06-03
PT77929B (en) 1986-04-16
JPS59130860A (ja) 1984-07-27
GR81705B (cs) 1984-12-12
PT77929A (en) 1984-02-01
ATE16797T1 (de) 1985-12-15
ES8507482A1 (es) 1985-09-01
AU2306084A (en) 1984-07-12
EP0113697A1 (en) 1984-07-18
DE3460012D1 (de) 1986-01-16
EP0113697B1 (en) 1985-12-04
AU567532B2 (en) 1987-11-26
DK5984A (da) 1984-07-08

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